title: Small molecule drug screening in Drosophila identifies the 5HT2A receptor as a feeding modulation target.
abstract: Dysregulation of eating behavior can lead to obesity, which affects 10% of the adult population worldwide and accounts for nearly 3 million deaths every year. Despite this burden on society, we currently lack effective pharmacological treatment options to regulate appetite. We used Drosophila melanogaster larvae to develop a high-throughput whole organism screen for drugs that modulate food intake. In a screen of 3630 small molecules, we identified the serotonin (5-hydroxytryptamine or 5-HT) receptor antagonist metitepine as a potent anorectic drug. Using cell-based assays we show that metitepine is an antagonist of all five Drosophila 5-HT receptors. We screened fly mutants for each of these receptors and found that serotonin receptor 5-HT2A is the sole molecular target for feeding inhibition by metitepine. These results highlight the conservation of molecular mechanisms controlling appetite and provide a method for unbiased whole-organism drug screens to identify novel drugs and molecular pathways modulating food intake.
authors.affiliation: The Rockefeller University, 1230 York Avenue, Box 63, New York, NY 10065, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gasque
authors.forename: Stephen
authors.initials: S
authors.lastname: Conway
authors.forename: Juan
authors.initials: J
authors.lastname: Huang
authors.forename: Yi
authors.initials: Y
authors.lastname: Rao
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Vosshall
mesh_terms: D000818:Animals; D001066:Appetite / Q000187:drug effects; D004330:Drosophila / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects*; D008719:Methiothepin / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D054852:Small Molecule Libraries
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D054852:Small Molecule Libraries; D008719:Methiothepin